Multiple sclerosis (MS) is a disease characterized by inflammation and demyelination in central nervous system white matter. MS affects 250,000 American and is thus the most important cause of neurologic disability, excluding trauma, that arises in early to middle adult life. Indirect evidence suggests that the immune system plays a role in the pathogenesis of MS, and data from family and twin studies indicate that genetic factors are important determinants of MS susceptibility. This study will attempt to establish the identity of genes that influence susceptibility to MS by linkage analysis using the affected sibling pair (sibpair) method. During the initial funding period 70 families, each with 2 or more siblings affected with typical MS, have been identified, and it is expected that 150 families will be studied during the course of the project. Inheritance of germline T-cell receptor beta chain (TCRbeta) genes that are identical by descent (IBD) will be determined by segregation analysis of polymorphic markers within the TCRbeta complex. Similar studies will be undertaken for genes that encode other TCR chains and the major histocompatibility complex (MHC). Epistatic interactions, should they be present, between candidate genes will be assessed. Allelic variants of TCRbeta variable region genes inherited by MS patients will be studied by single strand conformation polymorphism analysis in order to assess the possibility that a relevant gene segment may be responsible for haplotype sharing by sibpairs. In addition, the T-cell repertoire to myelin basic protein and proteolipid protein will be identified in siblings who have inherited MHC and TCRbeta genes that are IBD; these studies will define whether the T-cell response to these myelin proteins correlates with inheritance of TCRbeta and MHC genes IBD or with the presence of MS. The collection of a large genetic repository of sibpair MS families should also prove useful as an available resource for other studies of the inherited basis of MS susceptibility.